The effect of prehypertension and hypertension on the incidence of cardiovascular disease: A population‐based cohort study in Kharameh, a city in the South of Iran

Abstract Background and Aim Prehypertension and hypertension are important risk factors for cardiovascular diseases. This study was carried out to evaluate the effect of prehypertension and hypertension on the development of cardiovascular diseases. Methods This prospective cohort study was performed on 9442 people aged 40−70 in Kharameh, southern Iran. Individuals were divided into three groups: normal blood pressure (N = 5009), prehypertension (N = 2166), and hypertension (N = 2267). In this study, demographic data, disease histories, behavioral habits, and biological parameters were studied. At first, the incidence density was calculated. Then Firth's Cox regression models were used to investigate the association between prehypertension and hypertension with the incidence of cardiovascular diseases. Results The incidence density in the three groups of individuals with normal blood pressure, prehypertension, and hypertension was 1.33, 2.02, and 3.29 cases per 100,000 person‐days, respectively. The results of multiple Firth's Cox regression by controlling all factors showed that the risk of occurrence of cardiovascular disease in people with prehypertension was 1.33 times (hazard ratio [HR] = 1.32, 95% confidence interval [CI]: 1.01−1.73, p = 0.03) and those with hypertension were 1.85 times higher (HR = 1.77, 95% CI: 1.38−2.29, p < 0.0001) than the individuals with normal blood. Conclusion Prehypertension and hypertension have played an independent role in the risk for developing cardiovascular diseases. Therefore, early detection of individuals with these factors and control of other risk factors in them can contribute to reducing the occurrence of cardiovascular diseases.


| INTRODUCTION
Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. 1 The estimated number of patients and deaths caused by these diseases was 485.6 and 17.7 million annually, respectively. 2

Reports of the Global Burden of Disease (GBD) in 2019
showed that the number of patients and deaths due to CVDs doubled between 1990 and 2019. 3 Iran was introduced as one of the countries with the highest number of CVDs in the world due to the GBD report in 2015. 4 The most important preventive approaches for CVDs are changes in modifiable risk factors, including diabetes, hypertension, smoking, dyslipidemia, and low level of physical activity. 1 Changing these risk factors could reduce CVDs by approximately 90% around the world. 4 However, worldwide, Hypertension is an important risk factor for CVD, and it is the most prevalent risk factor. Tran et al., 5 The World Health Organization reported the number of people with hypertension to be 1.13 and 1.27 million deaths from CVDs attributed to hypertension billion (https://www.who.int/healthtopics/hypertension#tab=tab_1). In Iran, the prevalence of hypertension among people aged 40−70 years is 26.9%, and the risk attributed to hypertension for CVDs is estimated at 11.37%. 4 So far, several epidemiological studies have investigated the association between prehypertension and hypertension with CVDs in other parts of the world, that their results are contradictory. 2,6 However, there is currently no updated information on the subject. In addition, cohort studies that provide robust evidence are few in this regard.
Furthermore, in a literature review, we found no cohort studies that examined the association between prehypertension and hypertension with the incidence of CVDs in Iran. Meanwhile, having new and up-todate information from different regions of the world and identifying the exact role of prehypertension and hypertension in CVDs help health policymakers plan to develop interventional strategies for these people. Therefore, this study was conducted with a large sample size, a large number of risk factors compared to other studies, and by using the Firth's Cox regression model to reduce the error of estimates due to rare events, to accurately identify the role of hypertension and prehypertension in the occurrence of CVDs.

| Study population
This prospective study was based on the data from the Kharameh cohort study, which is a part of Prospective Epidemiological Studies in Iran (PERSIAN). The Persian cohort study was launched in 2014 to determine the prevalence and risk factors associated with noncommunicable diseases (NCDs) in 18 areas of Iran. Additional information are provided in other articles. 7 Kharameh is a city located in the southern region of Fars province. The people of this city have Persian ethnicity and race, and they also have customs and cultural traditions specific to their region. In addition, the lifestyle in the urban and rural areas of this city is somewhat similar.

| Data collection
The baseline data of the Kharameh cohort study were collected from March 2015 to March 2017, and, the information about the incidence of CVD in individuals has been collected during four stages of followup, in 2018, 2019, 2020, and 2021. Questionnaires from the Persian cohort study, which had already been validated, were used for data collection. The information related to these questionnaires as well as the data collection method is included in the Persian cohort study. 7 This study examined demographic information, behavioral habits, history of chronic diseases, anthropometric characteristics, and some biological parameters. The demographic information included age, sex, job status, marital status, place of residence, level of education, and socioeconomic status (SES). The Persian cohort questionnaires related to the individuals' assets were completed to assess their SES.
Physical activity levels were also assessed using standard questionnaires that measure daily activity. The calculation of the SES of people and the level of physical activity is also described in other studies of the Kharamah cohort. 9,10 Behavioral habits also included levels of physical activity, smoking, alcohol consumption, and anthropometric characteristics, including body mass index (BMI), waist circumference, and hip circumference. A history of diabetes, fatty liver, and chronic kidney disease was also evaluated. In addition, biological parameters, including low-density lipoprotein (LDL) and triglyceride (TG), were assessed. BMI was calculated by dividing weight (kg) by height in square meters (m 2 ), and individuals were divided into four classes. Underweight: BMI less than 18.5; normal: BMI between 18.5 and 24.9; overweight: BMI between 25 and 29.9; and obese: BMI above 30. 11

| Measurement and classification of blood pressure
Blood pressure was measured on the right upper arm of the subject in a sitting position after 5 min of rest. Blood pressure was taken from each individual twice at 10 min, and their mean was recorded as blood pressure. All measurements were performed using a standard calibration sphygmomanometer. Individuals were divided into three groups: individuals with normal blood pressure: blood pressure of SBP/DBP less than 120/80 mmHg; prehypertension group: SBP between 120 and 139 mmHg or DBP between 80 and 89 mmHg; and hypertension group: SBP/DBP above 140/90 mm/Hg. 12

| CVDs
In this study, the subjects were followed-up from the time of entry into the study to the time of the event or the end of the study. The incidence of CVDs was initially recorded using an interview based on their self-declaration. Then, their medical records were checked by physicians, and if were confirmed, they were registered as new cases of CVDs. If necessary, more diagnostic procedures were performed.
CVDs included coronary heart disease, cerebrovascular disease, rheumatoid arthritis, myocardial infarction, stroke, and heart valve disease.

| Statistical analysis
In the present study, the dependent variable was the time to event of CVDs. The time variable was calculated as the number of days between entry into the study and the occurrence of CVDs.
The participants were also considered the right censors if the event did not happen to them until the end of the study. Quantitative variables were described with mean and standard deviation, and qualitative variables were presented with numbers and percentages.
The Kolmogorov−Smirnov test assessed the normality of quantitative variables. The difference between the means of quantitative variables in three groups of individuals was examined using the ANOVA test and the difference between the levels of qualitative variables was examined using the χ 2 test. The incidence density was calculated on the basis of the person-day, which is the actual number of days individuals are at risk for CVDs. For the survival analysis, the Kaplan −Meier curve for the incidence of CVDs in the three groups of subjects was plotted. The log-rank test was calculated to compare the incidence of CVDs between these three groups. Also, we evaluated the effect of prehypertension and hypertension on the incidence of CVDs using three models in Firth's Cox regression. In the first model, the effect of prehypertension and hypotension was evaluated without adjusting for other variables. The second model was adjusted for age and sex variables, and the third model was adjusted for all variables with a p-value less than 0.2 in simple regression. The power of the association was reported with the hazard ratio (HR) with a 95% confidence interval (CI). All analyses were performed using R version 4.1.2, the "Coxphf" package.

| Distribution of baseline information
The present study was performed on 9442 individuals aged 40−70 years. They were divided into three groups: normal blood pressure F I G U R E 1 Flow chart of the study population.
T A B L E 1 Distribution of baseline characteristics in three groups of individuals with prehypertension, hypertension, and normal blood pressure in a population aged 40−70 years of Kharameh cohort study. (N = 5009), prehypertension (N = 2166), and hypertension (N = 2267). prevalence of fatty liver and diabetes was also significantly higher in the hypertension group than in the other two groups (p < 0.0001).
Further information is reported in Table 1.

| Duration of follow-up and occurrence of CVDs
In this study, the subjects were followed for 10,514,688 person-days in the normal blood pressure group, for 4,586,820 person-days in the prehypertension group, and 4,643,446 person-days in the hypertension group. The incidence density rate was estimated at 1.33 per 100,000 person-days in the normal blood group, 2.02 per 100,000 person-days in the prehypertension group, and 3.2 per 100,000 person-days in the hypertension group (Table 2). Figure 2 shows the CVDs survival curve for the three groups. The log-rank test showed that the risk of developing CVDs in the hypertension group was significantly higher than in the prehypertension and normal blood pressure groups (χ 2 = 63.03 p < 0.0001). between high blood pressure levels and the incidence of CVDs. 23 Generally, increasing blood pressure levels to prehypertension and hypertension increases the stress cycle on the main arteries, resulting in increased wear and tear of these arteries earlier, eventually leading to CVDs. However, the exact mechanism of the role of blood pressure in the development of CVDs remains unclear. Some studies suggest that hypertension has disrupted the regulation of the reninangiotensin and aldosterone systems through increased adiposity.

| Association between prehypertension and hypertension with the occurrence of CVDs
For this reason, adipokines and leptins increase and lead to the hardening of the arteries, eventually, the incidence of CVD increases.
On the other hand, prehypertension causes deformation of the left ventricle and a disorder of diastolic blood pressure, which ultimately increases the incidence of CVDs. 24 T A B L E 2 Incidence of cardiovascular disease in three groups of individuals with prehypertension, hypertension, and normal blood pressure in a population aged 40−70 years of Kharameh cohort study. It is also important to note that although the role of prehypertension and hypertension is recognized as an independent risk factor for the development of CVDs, if other risk factors accompany these factors, they increase the risk of developing CVDs more than when there is one factor alone. 25 However, many studies have shown that high BMI, LDL, TG, age, diabetes, and other risk factors for CVDs are more common in individuals with prehypertension and hypertension than in those with normal blood pressure. 6,22 In our study, the mean age of hypertensive was higher than prehypertensive patients and normal blood pressure subjects. Mean TG, LDL, and waist circumference were also higher among the hypertensive, prehypertensive subjects, and those with normal blood pressure, respectively. The prevalence of diabetes was also higher in hypertensive individuals. In addition, the prevalence of obesity and overweight was 68% in individuals with hypertension, 62% in individuals with prehypertension, and 52% in individuals with normal blood pressure. A cohort study conducted in China also showed that mean of TG, LDL, and BMI were higher in individuals with hypertension than those with normal blood pressure. 22 In Ajab Noor et al.'s study, subjects with hypertension and prehypertension compared to normal blood pressure had higher risk factors for CVDs, such as BMI, LDL, TG, and cholesterol. However, the association between blood pressure and CVDs can be reduced by modifying several risk factors. 25 Therefore, effective interventions in this field will significantly help to reduce the incidence of CVDs.

| Strengths and limitations
This is a prospective study with a large sample size that provides stronger evidence for investigating causality than retrospective and cross-sectional studies. We also adjusted a wide range of variables to investigate the independent role of prehypertension and hypertension in the incidence of CVDs. One of the limitations of the present study is the lack of access to some risk factors, such as people's nutritional status, environmental factors, and air pollution, which can play a role in the occurrence of CVDs. In addition, we did not have the data of various types of CVDs separately, which can also

ACKNOWLEDGMENTS
The authors are grateful to the officers and data management staff of Kharameh cohort. Also, the authors would like to thank all the study participants who patiently cooperated with us.

CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
The data sets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Abbas Rezaianzadeh had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.